For the treatment of blood-related diseases including leukemia as a typical example, it is extremely important to stably amplify and supply blood cells in an amount necessary for such treatment. Thus, to date, many researchers have attempted to efficiently amplify hematopoietic stem cells or hematopoietic progenitor cells. Among blood cells, megakaryocytes are cells capable of producing proplatelets, and further, platelets. Hence, the megakaryocytes play an important role in medical treatments.
Among blood cells, platelets are cells essential for blood coagulation (hemostasis). Accordingly, the demand for platelets is extremely high in the treatment of leukemia, bone marrow transplantation, anticancer therapy, etc. To date, the platelets have been supplied by a method of collecting blood from blood donors. However, it is difficult for the method of collecting blood from blood donors to stably supply platelets, since this method is problematic in terms of chronic shortage of donors, inability to preserve the collected platelets in a frozen state, etc. At the same time, other than the method of collecting blood from blood donors, a method of administering TPO to patients, a method of differentiating megakaryocytes from umbilical cord blood or myelocytes, etc. have been attempted. However, in the case of the method of administering TPO to patients, antibodies neutralizing the TPO are produced after the administration of the TPO. Thus, this method has not yet been put to practical use. Also, the method of differentiating megakaryocytes from umbilical cord blood or myelocytes is not suitable as a method of stably providing platelets because it is able to provide only small quantities of hematopoietic stem cells serving as a source of megakaryocytes.
In recent years, as a method for preparing platelets in vitro, there has been reported, for example, a method for efficiently differentiating hematopoietic stem cells or hematopoietic progenitor cells, which are induced from ES cells, into megakaryocytes and platelets. Eto et al. have clarified that mouse ES cells are co-cultured with OP9 stromal cells, so as to induce the differentiation of the mouse ES cells into megakaryocytes (Non-Patent Document 1). Fujimoto et al. have reported that they have confirmed the induction of platelets by applying a method similar to that of Eto et al. (Non-Patent Document 2). Moreover, there has been a report regarding a successful induction of the differentiation of monkey ES cells into megakaryocytes (Non-Patent Document 3), and there has also been a report regarding a successful induction of the differentiation of human ES cells into megakaryocytes (Non-Patent Document 4). However, in both cases, the release of platelets has not been confirmed. Furthermore, even in a case in which a method of obtaining platelets from ES cells has been established to such an extent that it can be clinically applied, when the platelets induced from ES cells are applied to patients via blood transfusion (wherein the application of the platelets may not become problematic after the initial transfusion, but if a single patient frequently receives transfusions,) problems regarding human leukocyte antigen (HLA) compatibility still remain.
iPS cells (induced pluripotent stem cells) may also be referred to as artificial pluripotent stem cells or induced type pluripotent stem cells. These are cells that have acquired pluripotent differentiation ability equivalent to that of ES cells by introducing several types of transcription factor genes into somatic cells such as fibroblasts.
Mouse iPS cells have been established for the first time by Yamanaka et al. by introducing four genes, Oct3/4, Sox2, Klf4 and c-Myc, into mouse fibroblasts, using the expression of a Nanog gene important for the maintenance of pluripotency as an indicator (Non-Patent Document 5). After that, several reports have been made concerning the establishment of mouse iPS cells by similar methods (Non-Patent Documents 6 and 7). Further, it has been reported that iPS cells can be established only using the three genes (Oct3/4, Sox2 and Klf4) other than the c-Myc gene, in order to overcome problems regarding the canceration of iPS cells (Non-Patent Document 8).
On the other hand, with regard to human iPS cells, Thomson et al. have introduced OCT3/4, SOX2, NANOG and LIN28 into human fibroblasts, so as to establish human iPS cells (Non-Patent Document 9). In addition, Yamanaka et al. have introduced OCT3/4, SOX2, KLF4 and cMYC into human fibroblasts, so as to establish iPS cells (Non-Patent Document 10).
Non-Patent Document 1: Eto et al., Proc. Acad. Sci. USA 2002, 99: 12819-12824.
Non-Patent Document 2: Fujimoto et al., Blood 2003, 102: 4044-4051.
Non-Patent Document 3: Hiroyama et al., Exp. Hematol. 2006, 34: 760-769.
Non-Patent Document 4: Gaur et al., J Thromb Haemost. 2005, 4: 436-442.
Non-Patent Document 5: Okita et al., Nature 2007, 448: 313-317.
Non-Patent Document 6: Wernig et al., Nature 2007, 448: 318-324.
Non-Patent Document 7: Maherali et al., Cell Stem Cell 2007, 1: 55-70
Non-Patent Document 8: Nakagawa et al., Nat. Biotechnol. 2008, 26: 101-106.
Non-Patent Document 9: Yu et al., Science 2007, 318: 1917-1920.
Non-Patent Document 10: Takahashi et al., Cell 2007, 131: 861-872.